Retinol Increases β-Catenin-RXRα Binding Leading to the Increased Proteasomal Degradation of β-Catenin and RXRα

Abstract

Retinol utilizes a retinoid X receptor (RXR)-mediated degradation pathway to decrease β-catenin protein in all-trans retinoic acid (ATRA)-resistant human colon cancer cells. In this study, we examined interactions between RXRα and β-catenin in ATRA-resistant human colon cancer cells treated with retinol. Retinol treatment triggers relocation of β-catenin and RXRα proteins. Cells treated with retinol for 8 and 24 h displayed increased cytosolic but decreased nuclear β-catenin and RXRα. Retinol treatment increased β-catenin and RXRα protein interaction. Previously, we showed that 24 h of retinol treatment increased RXRα protein. Here we show this increase in RXRα levels is due to increased RXRα messenger RNA. Treatment with 48 h with retinol decreased RXRα protein levels. Last, by transfecting HCT-116 cells with a RXRα construct lacking the activation function-1 and DNA binding domains, we show RXRα and β-catenin binding is required for proteosomal degradation of β-catenin. These results suggest retinol induces RXRα and β-catenin binding and transport to the cytosol where they are proteasomally degraded.

ACKNOWLEDGMENTS

The authors would like to thank Dr Ron Evens (Salk Institute, La Jolla, CA) for generously providing the RXRα plasmid. This research was supported by the American Cancer Society Grant No. RSG–03–233–01–CNE.